Dialysate regeneration unit

ABSTRACT

A dialysate regeneration unit adapted for regenerating a dialysate containing carrier substances comprises a first flow path and a second flow path. The first flow path comprises a first supply unit adapted for adding an acidic fluid to the dialysate flowing in the first flow path, and a detoxification unit located downstream of the first supply unit. The detoxification unit is adapted for removing toxins from the acidified dialysate flowing in the first flow path. The second flow path extends in parallel to the first flow path. The second flow path comprises a second supply unit adapted for adding an alkaline fluid to the dialysate flowing in the second flow path, and a further detoxification unit located downstream of the second supply unit. The further detoxification unit is adapted for removing toxins from the alkalized dialysate flowing in the second flow path.

The present invention relates to a dialysate regeneration unit adaptedfor regenerating a dialysate containing carrier substances. Theinvention further relates to a dialysis system, and to a method forregenerating a dialysate containing carrier substances.

When liver or kidney of a human being fail to perform their normalfunctions, inability to remove or metabolise certain substances resultsin their accumulation in the body. These substances can bedifferentiated according to their solubility in water: Water-soluble andwater-insoluble (or protein-bound). Different extracorporeal proceduresare available to help replace the failing functions. Hemodialysis is thegold standard for treating patients with renal failure. For thispurpose, a dialyzer is used which is divided into two compartments by asemipermeable membrane. Blood is passed through the blood compartment ofthe dialyzer separated by the semipermeable membrane from dialysis fluidwhich passes through the dialysis compartment of said dialyzer. Aphysiological dialysis fluid should comprise the desired electrolytes,nutrients and buffers in concentrations so that their levels in thepatient's blood can be brought to normal.

The routine hemodialysis is of little help for patients with liverfailure especially when they have no accompanying renal failure. This ismainly due to the fact that the main toxins like metabolites, e.g.bilirubin, bile acids, copper and other substances like gases, hormonesor drugs accumulating in hepatic failure are protein-bound and thereforehardly removed by hemodialysis.

In order to enhance the removal of the protein-bound substances, thedialysis fluid composition is modified to comprise albumin, which bindsto the unbound toxins travelling from blood to the dialysate across thesemipermeable membrane. The mode of treatment is then called “albumindialysis”. The presence of albumin in the dialysate facilitates theremoval of protein-bound substances from blood. The use of albumin isbased on its being the main carrier protein for protein-bound toxins inthe blood.

However, the commercially available albumin is very expensive.Therefore, albumin-based systems incur high treatment costs.Furthermore, these systems offer an unsatisfactory detoxificationefficiency: on average only up to 30% reduction of the bilirubin levelas a marker for protein-bound substances can be achieved. Although thealbumin-based dialysis processes bring about an improvement in thesymptoms of hepatic encephalopathy, a normalization of the values cannotbe achieved as a consequence of the limited detoxification efficacy andhigh treatment costs.

US patent application US 2005/0082225 A1 relates to a means of dialysisfor removing protein-bound substances from a biological fluid,especially blood or blood plasma, which contains at least one means forsolubilizing protein-binding substances to be removed into thebiological fluid and/or dialysis fluid, and to a process for removingprotein-bound substances from a biological fluid.

It is an object of the invention to provide an improved apparatus andmethod for regenerating a dialysate containing carrier substances.

The object of the invention is solved by a dialysate regeneration unitaccording to claim 1, a dialysis system according to claim 26, and by amethod for regenerating a dialysate containing carrier substancesaccording to claim 35.

A dialysate regeneration unit according to embodiments of the presentinvention, which is adapted for regenerating a dialysate containingcarrier substances, comprises a first flow path and a second flow path.The first flow path comprises a first supply unit adapted for adding anacidic fluid to the dialysate flowing in the first flow path, and adetoxification unit located downstream of the first supply unit. Thedetoxification unit is adapted for removing toxins from the acidifieddialysate flowing in the first flow path. The second flow path extendsin parallel to the first flow path. The second flow path comprises asecond supply unit adapted for adding an alkaline fluid to the dialysateflowing in the second flow path, and a further detoxification unitlocated downstream of the second supply unit. The further detoxificationunit is adapted for removing toxins from the alkalised dialysate flowingin the second flow path.

For dialyzing patients with liver failure, a dialysis fluid containingcarrier substances like e.g. albumin is employed. A dialysis fluid ofthis kind is generally quite expensive. For cleaning and regeneratingthe dialysis fluid, toxins binding to the carrier substances have to beremoved. For efficiently removing said toxins, the dialysateregeneration unit according to embodiments of the present inventioncomprises two flow paths that are fluidically connected in parallel. Thedialysate to be regenerated is split up and conveyed through the twoflow paths. In the first flow path, an acidic fluid is added to thedialysate. For toxins that are soluble in acidic solution, theconcentration of free toxins in solution is increased. In thedetoxification unit located downstream of the acidic fluid supply unit,the free toxins are removed from the acidified dialysate flowing in thefirst flow path. By adding an acidic fluid to the dialysate, removal ofacidic soluble toxins is facilitated. Furthermore, by decreasing the pH,alkaline soluble toxins may e.g. be precipitated and thereby removedfrom the dialysate fluid.

In the second flow path, which extends in parallel to the first flowpath, an alkaline fluid is added to the dialysate flowing in the secondflow path. Due to the increase of the pH, the concentration of freealkaline soluble toxins is increased, and thus, removal of alkalinesoluble toxins is facilitated. These toxins are removed by a furtherdetoxification unit, which is located downstream of the alkaline fluidsupply unit. The further detoxification unit is adapted for removingtoxins from the alkalized dialysate flowing in the second flow path.Furthermore, by increasing the pH, acidic soluble toxins may e.g. beprecipitated and thereby removed from the dialysate fluid.

By providing an acidic flow path and an alkaline flow path in parallel,both acidic soluble toxins and alkaline soluble toxins may beefficiently removed from the dialysate. Hence, the dialysateregeneration unit according to embodiments of the present invention iscapable of efficiently removing protein-binding toxins. The term “toxin”is understood very broadly here and additionally covers allprotein-binding substances which normally are not directly referred toas toxins, such as drugs, electrolytes, hormones, fats, vitamins, gases,and metabolic degradation products like bilirubin.

Downstream of the detoxification units, the regenerated acidifieddialysate from the first flow path may be merged with the regeneratedalkalized dialysate from the second flow path, whereby the acidifieddialysis fluid from the first flow path and the alkalized dialysis fluidfrom the second flow path may neutralize one another at least partially.Hence, by merging the flow of acidified dialysate from the first flowpath with the flow of alkalized dialysate from the second flow path, aflow of regenerated dialysate at a physiological pH value may beprovided. Furthermore, the exact pH value of the regenerated dialysatemay be adjusted by regulating the respective flows conveyed through thefirst and the second flow path. Hence, the dialysate regeneration unitaccording to embodiments of the present invention is capable ofproviding a regenerated dialysis fluid at a physiological pH value.

According to a preferred embodiment, the acidic fluid added by the firstsupply unit comprises at least one of: hydrochloric acid, sulfuric acid,acetic acid.

Preferably, the alkaline fluid added by the second supply unit comprisesat least one of: sodium hydroxide solution, potassium hydroxidesolution.

Further preferably, the acidic fluid and the alkaline fluid are chosensuch that “physiological” neutralization products are generated duringneutralization. For example, a certain concentration of the occurringneutralization products might already be present in the respectivebiological fluid anyway. For example, when using aqueous hydrochloricacid and aqueous sodium hydroxide solution, a certain concentration ofNaCl is produced during neutralization of the acidified flow and thealkalized flow. NaCl is also present in a biological fluid like e.g.blood or blood serum.

In a preferred embodiment, the first supply unit is adapted foradjusting the pH of the dialysate in the first flow path to a pH between1 and 7, preferably between 2.5 and 5.5.

In a preferred embodiment, the second supply unit is adapted foradjusting the pH of the dialysate in the second flow path to a pHbetween 7 and 13, preferably between 8 and 13.

According to a preferred embodiment, by decreasing the pH of thedialysate in the first flow path, a concentration ratio oftoxin-carrier-complex to free toxin and free carrier substance isshifted in favour of the free toxin for at least some of the toxins inthe dialysate, thereby increasing a concentration of free toxins in thedialysate. By decreasing the pH of the dialysate in the first flow path,the solubility of acidic soluble toxins (like e.g. magnesium or copper)is increased, whereas the binding affinity between the acidic solubletoxins and the carrier substances is reduced. Accordingly, theconcentration of free toxins in solution is increased.

Further preferably, the detoxification unit is adapted for at leastpartially removing said free toxins. Due to the increased concentrationof free toxins, said toxins may be removed at an increased rate.

Furthermore, by decreasing the pH value of the dialysate in the firstflow path, some of the alkaline soluble toxins may e.g. be precipitatedand thereby removed from the dialysate fluid.

In a preferred embodiment, by increasing the pH of the dialysate in thesecond flow path, a concentration ratio of toxin-carrier-complex to freetoxin and free carrier substance is shifted in favour of the free toxinfor at least some of the toxins in the dialysate, thereby increasing aconcentration of free toxins in the dialysate. By increasing the pH ofthe dialysis fluid in the second flow path, solubility of alkalinesoluble substances (like e.g. bilirubin) is increased, whereas thebinding affinity between the alkaline soluble toxins and the carriersubstances is reduced. Accordingly, the concentration of free toxins insolution is increased.

Preferably, the further detoxification unit is adapted for at leastpartially removing said free toxins. Due to the increased concentrationof free toxins, said toxins may be removed at an increased rate.

Furthermore, by increasing the pH value of the dialysate in the secondflow path, some of the acidic soluble toxins may e.g. be precipitatedand thereby removed from the dialysate fluid.

According to a preferred embodiment, at least one of the first and thesecond flow path comprises a temperature regulation unit locatedupstream of the detoxification unit, e.g. the filtration device, thetemperature regulation unit being adapted for increasing or decreasingthe temperature of the dialysate. For example, heating or cooling of thedialysate may further enhance the above-described effects.

According to a further preferred embodiment, by increasing thetemperature of the dialysate, the concentration ratio oftoxin-carrier-complex to free toxin and free carrier substance isshifted in favour of the free toxin for at least some of the toxins inthe dialysate, thereby increasing a concentration of free toxins in thedialysate. Accordingly, the free toxins may be removed at an increasedrate by the detoxification units.

Preferably, the toxins comprise one or more of: metabolism products,bilirubin, bile acid, drugs, electrolytes like e.g. magnesium, hormones,lipids like e.g. free fatty acids, vitamins, phenols, sulfates,minerals, trace elements like e.g. copper, iron, selenium, manganese,gases like e.g. nitric oxide or carbon monoxide.

Further preferably, the carrier substances comprise one or more of:albumin, human serum albumin, animal albumin, genetically engineeredalbumin, globulins, lipoproteins, carbon particles. Mixtures containingalbumin and at least one further carrier substance are preferred.Moreover, carrier substances may be chosen from substances which changetheir binding capacity/affinity (e.g. due to a conformational change) totoxins in dependency upon various physico-chemical parameters, e.g. pHand/or temperature and/or light (wavelength) and/or pressure, inparticular change their binding capacity to toxins to be removed fromthe dialysis fluid circuit. Such carrier substances allow the carriersubstances to bind to toxins under predertermined conditions, while theymay be recycled by modifying the conditions. Under modified conditionsthe complex of carrier substance and toxin dissociates, which allows thecarrier substance to be re-introduced into the dialysis fluid circuit.The toxin is removed by e.g. a precipitation reaction or by thedetoxification unit as such, e.g. by diafiltration (s. above). Examplesfor carrier substances exhibiting the property of (reversibly) binding(dependent on the physico-chemical properties) to a specific toxin maybe selected according to the character of the toxin to be bound. Ingeneral, glycosides, nucleic acids (and their derivatives), fatty acids,fats, carbon molecules, nanoparticles, memory plastics, memory metals,proteins, resins, secondary plant substances or other complex compoundsderived from natural sources, carbon hydrates or synthetic compounds,e.g. polymers, exhibiting this property.

According to a preferred embodiment, the detoxification unit and thefurther detoxification unit are implemented as regeneration dialyzers,or as ultrafiltration devices, or as diafiltration devices or as devicesallowing a precipitation reaction to occur. In case the detoxificationunits are implemented as dialyzers, toxins may be passed to a dischargefluid via a semipermeable membrane.

In a preferred embodiment, the detoxification unit and the furtherdetoxification unit each comprise a filtration pump and a dischargeconduit adapted for withdrawing a discharge fluid from the respectivedetoxification unit. In the detoxification units, the toxins are passedto the discharge fluid. In the discharge fluid, the toxin concentrationis increased, whereas in the dialysate, the toxin concentration isreduced.

Preferably, the first flow path comprises a first pump adapted forpumping the dialysate through the first flow path, and the second flowpath comprises a second pump adapted for pumping the dialysate throughthe second flow path, the first and the second pump operatingindependently of one another. Flow characteristics in the first flowpath may differ from flow characteristics in the second flow path. Forexample, in an acidic environment, a carrier substance like albumin mayhave a different shape than in an alkaline environment. As aconsequence, the flow resistance in the first flow path may differ fromthe flow resistance in the second flow path. By providing two separatepumps, these differences may be compensated for, and an equal flow ofdialysis fluid in the first and the second flow path may beaccomplished.

According to a preferred embodiment, the acidified dialysate supplied bythe first flow path is merged with the alkalised dialysate supplied bythe second flow path. Downstream of the supply units and thedetoxification units of the first and the second flow path, the twoflows are merged, and a unified flow of regenerated dialysis fluid isgenerated.

Further preferably, when the acidified dialysate supplied by the firstflow path is merged with the alkalised dialysate supplied by the secondflow path, the acidified dialysate and the alkalised dialysateneutralize each other at least partially.

According to a preferred embodiment, the dialysate regeneration systemcomprises a plurality of switching valves.

Preferably, during a first phase of operation, the switching valves areset such that a first detoxification unit is included in the first flowpath and that a second detoxification unit is included in the secondflow path, whereas during a second phase of operation, the switchingvalves are set such that the second detoxification unit is included inthe first flow path and that the first detoxification unit is includedin the second flow path.

Preferably, the switching valves are operated such that the acidifieddialysate is alternatingly supplied to a first detoxification unit andto a second detoxification unit, whereas the alkalised dialysate isalternatingly supplied to the second detoxification unit and to thefirst detoxification unit.

During the first phase of operation, the first detoxification unit isexposed to a flow of acidic fluid. During this phase of operation,acidic soluble substances, like e.g. magnesium, may be removed from thedialysate. However, other substances, which are insoluble in an acidicenvironment, might be precipitated during the first phase of operationand thereby removed from the dialysis fluid. The second detoxificationunit is exposed to an alkaline environment during the first phase ofoperation. Accordingly, alkaline soluble substances, like e.g.bilirubin, may be removed from the dialysate and substances that areinsoluble in alkaline solution may be precipitated in the seconddetoxification unit. Precipitation of insoluble substances may impairproper functioning of the detoxification units. For example,precipitated substances may lead to clogging of the detoxificationunits. Hence, it is proposed that during a second phase of operation,the switching valves are set such that the first detoxification unit andthe second detoxification unit are interchanged. Now, the seconddetoxification unit is included in the first flow path, and the firstdetoxification unit is included in the second flow path. Accordingly,the first detoxification unit is exposed to an alkaline environment, andacidic insoluble substances that have been precipitated during the firstphase of operation may be solubilized and removed from the dialysisfluid. Vice versa, the second detoxification unit is exposed to anacidic environment, which implies that alkaline insoluble substancesthat have been precipitated during the first phase of operation can bedissolved and removed from the second detoxification unit. Byperiodically exchanging the first and the second detoxification unit,precipitated substances can be removed, and proper functioning of thedetoxification units is ensured over a long period of time. Thus, thelife span of the detoxification units is prolongated and the removal oftoxins from the dialysate is increased.

According to a preferred embodiment, the switching valves are switchedperiodically. Thus, an accumulation of precipitated substances isavoided.

Further preferably, the switching valves are automatically switched atregular time intervals, preferably every 30 to 60 minutes. For example,the dialysate regeneration unit might comprise an electronic controlunit adapted for controlling operation of the switching valves.

A dialysis system according to embodiments of the present inventioncomprises a biological fluid circuit, a dialysate circuit, at least onedialyzer, and a dialysate regeneration unit as described above.

In a preferred embodiment, the biological fluid is blood or bloodplasma.

In a preferred embodiment, the dialysis system comprises a dialysatereservoir, that is part of the dialysate circuit, wherein the dialysateregeneration unit is adapted for withdrawing dialysate from thedialysate reservoir, for regenerating the dialysate, and for resupplyingthe regenerated dialysate to the dialysate reservoir.

The dialysate reservoir may act as a buffer reservoir between the bloodcleaning circuit and the dialysate regeneration unit. The supply ofdialysate to one or more dialyzers of the blood cleaning circuit may beimplemented either from the dialysate reservoir or directly from theregeneration circuit, e.g. by splitting the regenerated dialysate flowinto two conduits—the first leading to the dialysate reservoir and thesecond leading to the dialyzers of the blood cleaning circuit. Byproviding a dialysate reservoir, the dialysate circuit may be decoupledfrom the dialysate regeneration unit. For example, the flow rate in thedialysate circuit may be chosen independently of the flow rate throughthe dialysate regeneration unit. In particular, the flow rate in thedialysate regeneration unit may e.g. be higher than the flow rate in theblood cleaning circuit. Furthermore, in the dialysate regeneration unit,cleaning of the dialysate may be carried out under non-physiologicaloperating conditions. By providing a dialysate reservoir and decouplingthe dialysate regeneration unit from the blood cleaning circuit, anefficient protection of the patient's blood is accomplished.

According to a preferred embodiment, the dialysate regeneration unit ispart of a separate dialysate regeneration circuit.

According to a further preferred embodiment, the regeneration unit isadapted for regenerating the dialysate in a continuous operation or inan intermittent operation. Due to the presence of the dialysatereservoir, an intermittent operation of the dialysate regeneration unitis possible.

According to an alternative embodiment, the dialysate regeneration unitis integrated into the dialysate circuit. In this embodiment, the flowof regenerated dialysate is directly supplied to the dialyzers.

Preferably, the dialyzer comprises a biological fluid compartment thatis part of the biological fluid circuit, a dialysate compartment that ispart of the dialysate circuit, and a semipermeable membrane separatingthe biological fluid compartment and the dialysate compartment.

The dialysis system further comprises a substitution unit adapted forsupplying substitution fluid to the biological fluid or to thedialysate. For example, by adding substitution fluid, the volume of thebiological fluid or dialysate may be increased. Furthermore, thesubstitution fluid may comprise substances like e.g. electrolytes,nutrients, buffer, and other important substances, which may not havethe appropriate concentrations in the biological fluid or in thedialysate. The physiological dialysis fluid and the substitution fluidshould complement one another, whereby the aim is that the cleaned bloodreturned to the patient has electrolytes, nutrients, buffers, and otherimportant substances in physiological concentrations.

For a better understanding of the present invention and to show how thesame may be carried into effect, reference will now be made by way ofexample to the accompanying drawings in which

FIG. 1 is a schematic block diagram of a dialysis system according to anembodiment of the present invention;

FIG. 2A is a more detailed view of a dialysis system according to anembodiment of the present invention, and

FIG. 2B shows another embodiment of the invention, wherein the dialysissystem comprises a dialysate reservoir.

FIG. 1 shows a schematic block diagram of a dialysis system according toan embodiment of the present invention. Via an arterial blood line 1,blood from a patient is supplied to a dialyzer 2. Before the blood issupplied to the dialyzer 2, a predilution fluid 3 is added to the blood.In the dialyzer 2, the respective flows of blood and dialysate may beconducted in concurrent flow, as shown in FIG. 1. Alternatively, therespective flows of blood and dialysate may be conducted in counterflow.At the dialyzer 2, diffusion, convection and/or ultrafiltrationprocesses take place, and the patient's blood is cleaned. After theblood has passed the dialyzer 2, a postdilution fluid 4 is added to thecleaned blood. The cleaned blood is resupplied to the patient via avenous blood line 5.

The dialysis system comprises a dialysate regeneration circuit 6 adaptedfor regenerating dialysate that has passed through the dialyzer 2. Inembodiments of the present invention, a dialysate that contains carriersubstances like e.g. albumin is used. In particular, the dialysateregeneration circuit 6 is adapted for removing protein-binding toxinslike e.g. bilirubin, bile acid, etc. from the dialysate. First, one ormore fluids 7 are added to the dialysate. Then, fluids 8 are removedfrom the dialysate, e.g. by filtration, diafiltration, precipitation ordialysis under certain pH and temperature conditions. Furthermore, oneor more substitution fluids 9 may be added to correct the concentrationof the electrolytes and other important substances in the dialysate.From the dialysate regeneration circuit 6, a flow of regenerateddialysate is supplied to the dialyzer 2.

FIG. 2A gives a more detailed view of an embodiment of a dialysis systemaccording to the present invention.

The dialysis system comprises a blood circuit 11 with two dialyzers 12Aand 12B. Each of the dialyzers 12A and 12B comprises a bloodcompartment, a dialysate compartment, and a semipermeable membrane 13A,13B that separates the compartments. The dialyzers 12A, 12B arefluidically connected in parallel. Blood from the patient is passedthrough the tubings via a blood pump 14. Before the blood is supplied tothe dialyzers 12A, 12B, a predilution fluid 15 is added to the blood viaa predilution pump 16. Then, the blood is passed through the bloodcompartments of the dialyzers 12A, 12B. Before the cleaned blood isreturned to the patient, a postdilution fluid 17 is added to the bloodvia a postdilution pump 18.

Blood flow rates can be between 100-600 ml/min but are preferablybetween 150-400 ml/min, more preferably between 150-250 ml/min.Predilution flow rates can be between 1-20 l/h but are preferablybetween 4-7 l/h. Postdilution flow rates can be between 5-30% of thechosen blood flow rates, but are preferably between 10-20%.

In the embodiment shown in FIG. 2A, the dialysate circuit comprises adialysate regeneration unit 19. Dialyzing fluid that has been passedthrough the dialysate regeneration unit 19 is pumped into the dialysatecompartments of the dialyzers 12A, 12B with a first dialysate pump 20 ata flow rate between 150-2000 ml/min but preferably between 500-1100ml/min. In order to bring the electrolytes and other importantsubstances to desired concentrations, substitution fluids 21, 22 may besupplied to the dialysate via respective pumps 23, 24. After passingthrough the dialysate compartments of the dialyzers 12A, 12B, thedialyzing fluid with the added fluids taken from the patient to reducehis volume overload are transported to the dialysate regeneration unit19 via a second dialysate pump 25.

According to embodiments of the present invention, the dialysateregeneration unit 19 comprises two flow paths 27, 28 that arefluidically connected in parallel. In flow path 27, which will furtheron be referred to as the “acidic flow path”, an acidic solution 29comprising a strong acid is added to the dialysis fluid via an acid pump30. In flow path 28, which will further on be referred to as the“alkaline flow path”, an alkaline solution 31 comprising a strong baseis added to the dialysis fluid via a base pump 32.

The dialysate regeneration unit 19 comprises two regeneration pumps 33,34 for transporting the dialysate through the two flow paths 27, 28.Preferably, two separate pumps are used for the transport of thedialysis fluid, because the resistance of the fluid can be different inthe acidic flow path 27 and in the alkaline flow path 28. For example, acarrier substance like e.g. albumin might have a different shape inacidic or alkaline conditions and therefore different flowcharacteristics for different pH values. Alternatively to two pumps, asystem with clamps and fluid measurements can be used to achieveconstant flow rates in the two flow paths 27 and 28.

Each of the two flow paths 27, 28 comprises a detoxification unit 35, 36adapted for filtering or dialysing the dialysate, and for removingtoxins from the dialysate. The detoxification units 35, 36 might e.g. beimplemented as regeneration dialyzers, ultrafiltration units,diafiltration units, etc. The regeneration pump 33 of the acidic flowpath 27 and the regeneration pump 34 of the alkaline flow path 28transfer the dialysate downstream to one of two detoxification units 35,36 of the dialysate regeneration unit 19. The dialysate is supplied tothe detoxification units 35, 36 via a valve mechanism comprisingswitching valves 37, 38.

In the detoxification unit through which alkaline solution is flowing,alkaline soluble toxins like e.g. bilirubin can be removed by filtrationor dialysis. Under alkaline conditions, the concentration of alkalinesoluble toxins in solution is increased. Due to this concentrationincrease of free toxins, removal of the free toxins is facilitated.

In the other detoxification unit through which acidic solution isflowing, these alkaline soluble toxins may e.g. be precipitated andthereby removed from the dialysis fluid.

With regard to acidic soluble toxins like e.g. magnesium, a similareffect is observed. In an acidic solution, the concentration of acidicsoluble toxins in solution is increased, and hence, acidic solubletoxins may be removed at an increased rate. In contrast, in thedetoxification unit through which alkaline solution is flowing, theacidic soluble toxins are precipitated, e.g. as magnesium hydroxide, andthereby removed from the dialysis fluid.

The switching valves 37, 38 are adapted for changing the direction ofthe acidified dialysis fluid transported by the regeneration pump 33 onthe acidic side either towards the detoxification unit 35 or towards thedetoxification unit 36 (switching valves 37) and changing the directionof the alkalised dialysis fluid transported by the regeneration pump 34on the alkaline side either towards the detoxification unit 36 ortowards the detoxification unit 35 (switching valves 38). The switchingvalves 37, 38 change the direction of flow e.g. every 30-60 minutes sothat each detoxification unit 35, 36 receives fluid from one of theregeneration pumps 33 and 34 at a time. However, change of direction offlow may occur every 1 to 60 min depending on the acid used and themechanism applied. Switching may be performed automatically orindividually be the user. Change of direction very 1 to 10, preferablyevery 1 to 5 min may be preferred for certain applications.

Depending on the filtration type, the precipitated substances can causean occlusion of the detoxification units 35, 36 by blocking the pores ofthe detoxification unit 35, 36. To avoid this, the detoxification units35, 36 are alternated: the detoxification unit that is in one timeperiod (e.g. for 30 min) the acidic detoxification unit is in thefollowing time period (e.g. 30 min) used in the alkaline flow path. Thismeans that then precipitated substances are solved and removed with highconcentration by filtration or dialysis. This also enables continuoususe of the detoxification units over a long time period.

The switching of the detoxification units 35, 36 may e.g. be donemanually, or by a valve mechanism that is electronically controlled. Theswitching may be performed at different locations in the fluid circuit,the most preferable location being directly upstream of thedetoxification units 35, 36. However, the temperature regulation unit53, 54 may be located in the circuit and/or controlled in a way, whichallows them to be included into the switching mechanism acting on thedetoxification units. The change of the direction of the e.g. acidifieddialysis fluid may be established together with the change of directionof the acidified fluid in the detoxification units 35, 36. However, anindependent change of direction of the e.g. acidified dialysis fluid inthe temperature regulation units 53, 54 and the detoxification units 35,36 may also be realized. By including the temperature regulation unitsin the switching mechanism, it is ensured that the both units do notaccumulate precipitated carrier substances, e.g. albumin, which may becaused by exclusively contacting the temperature regulation units 53, 54with either alkalised or acidified dialysis fluid, in particular due totemperature effects at this unit.

For removing fluids and toxins from the detoxification units 35, 36, thesystem comprises two filtrate pumps 39, 40 operative to remove dischargefluids 41, 42 from the detoxification units 35, 36. For balancing thevolumes of the different fluids, the system may comprise a plurality ofscales 43-46 adapted for constantly measuring the fluid volume of theadded acid 29, of the added base 31 and of the discharge fluids 41, 42.

Downstream of the detoxification units 35, 36, the flow of regeneratedacidified dialysate obtained at the outflow of one of the detoxificationunits is merged with the flow of regenerated alkalised dialysateobtained at the outflow of the other detoxification unit. By merging theacidified flow with the alkalised flow, the acid and the base neutralizeeach other, and a flow of regenerated dialysate with a pH in thephysiological range between 6 and 8 is generated. The regenerateddialysate may be supplied to the dialyzers 12A, 12B. A temperatureregulation unit may be located in the dialysis fluid circuit before thedialysate passes to the dialyzers 12A, 12B. This allows the recycleddialysis fluid to be adjusted to the temperature needed for contactingthe blood at the membrane of the dialyzers 12A, 12B.

Preferably, in the acidic flow path 27 and in the alkaline flow path 28,acids or bases are added whose conjugate bases or acids are ions thatoccur naturally in the human organism. Thus, it is made sure that theregenerated dialysate obtained by merging the acidified flow ofdialysate and the alkalised flow of dialysate does not contain anynon-physiological substances.

Various system parameters like e.g. pH value, temperature, andconductivity of the dialysate are monitored via sensors 47-50 located onthe base and the acid side upstream of the detoxification units 35, 36.In the acidic flow path 27, sensors 47 monitor the system parametersbefore adding the acid and sensors 48 measure the system parametersafter adding the acid. Accordingly, in the alkaline flow path 28,sensors 49 monitor the system parameters before adding the base andsensors 50 measure the system parameters after adding the base.

The system may comprise further sensor units 51, 52 located in thedischarge flow paths of the detoxification units 35, 36. The sensorunits 51, 52 are adapted for monitoring system parameters like e.g. pHvalue, temperature and conductivity.

In each of the flow paths 27, 28, further process steps for at leasttemporarily increasing the concentration of free toxins in the dialysatemay be realized, in order to enhance the removal of toxins. Theseprocess steps may e.g. include one or more of the following: heating orcooling the dialysate, irradiating the dialysate with waves, changingthe salt content of the dialysate, adding a dialysable substance bindingto the toxins to be removed.

In the embodiment shown in FIG. 2A, each of the flow paths 27, 28comprises a respective temperature regulation unit 53, 54. For example,heating of the dialysate may be helpful for weakening the bond betweenthe protein-binding toxins and the carrier substances. The heating maye.g. be effected via direct heating of the fluidfilled tubing system, orby irradiation with microwaves or infrared. Alternatively, thetemperature regulation units may be adapted for cooling the dialysate.By changing the temperature of the dialysis fluid, the concentration offree toxins in solution is increased and accordingly, removal of toxinsis enhanced.

Another possible process step for changing the concentration ratio oftoxin-carrier-complex to free toxin and free carrier substance is toirradiate the dialysate with waves. For example, an ultrasonic apparatusmay be used as the device for irradiating with waves. Other appropriatedevices may e.g. be those suitable for generating light waves,ultraviolet waves, infrared waves, radio waves and microwaves.

Another possible process step for changing the concentration ratio oftoxin-carrier-complex to free toxin and free carrier substance is tochange the salt content of the dialysate. Changing the saltconcentration may help to solubilize the toxins to be removed. Moreover,it can also be used to restore the binding capacity of recycled carriersubstances for toxins. The addition of urea may be necessary to improvethe binding capacity of the carrier substances.

Another possible process step for changing the concentration ratio oftoxin-carrier-complex to free toxin and free carrier substance is to adddialysable compounds to the dialysate, said dialysable compounds beingadapted to bind to the toxins to be removed. Binding compounds which canbe used are dialysable compounds of low/intermediate molecular weightthat are distinguished by a strong affinity for the substances to beremoved. The preferred compounds include caffeine, which binds tobilirubin, and common chelating agents like penicillamine, trientine,deferoxamine, preferiprone, HBED, vitamin C, BAL, DMPS or DMSA, whichbind to metal cations such as copper ions or iron ions.

FIG. 2B shows an alternative embodiment of a dialysis system. Thedialysis system comprises a blood circuit 53 with two dialyzers 54A and54B. Each of the dialyzers 54A and 54B comprises a blood compartment, adialysate compartment, and a semipermeable membrane 55A, 55B thatseparates the compartments. The dialyzers 54A, 54B are fluidicallyconnected in parallel. Blood from the patient is pumped through theblood compartments of the dialyzers 54A, 54B by a blood pump 56.

The embodiment of FIG. 2B comprises a dialysate reservoir 57 for storingregenerated dialysate. Dialysis fluid from the dialysate reservoir 57 ispumped through the dialysate compartments of the dialyzers 54A, 54B by afirst dialysate pump 58. In order to bring the electrolytes and otherimportant substances to desired concentrations, substitution fluids 59,60 may be supplied to the dialysate via respective pumps 61, 62. Afterpassing through the dialysate compartments of the dialyzers 54A, 54B,the dialyzing fluid with the added fluids taken from the patient aresupplied to the dialysate reservoir 57 via a second dialysate pump 63.

From the dialysate reservoir 57, a flow of dialysate is provided to adialysate regeneration unit 64. The internal set-up of the dialysateregeneration unit 64 is identical to the internal set-up of thedialysate regeneration unit 19 shown in FIG. 2A. The dialysateregeneration unit 64 comprises two flow paths, an acidic flow path andan alkaline flow path, which are fluidically connected in parallel. Eachof the flow paths comprises a detoxification unit.

In the embodiment shown in FIG. 2B, a separate dialysate regenerationcircuit 65 is provided for regenerating the dialysis fluid contained inthe dialysate reservoir 57.

The dialysate regeneration circuit 65 (tertiary circuit) is decoupledfrom the blood cleaning circuit. The blood cleaning circuit comprisesthe blood circuit 53 (primary circuit) and the dialysate circuit(secondary circuit). By decoupling the dialysate regeneration circuitfrom the dialysate circuit, system parameters like flow, temperature andpH are independently adjustable to the needs of the two differentprocesses. For example, dialysate flow during the blood cleaning processmay be between 150-2000 ml/min, whereas during the regeneration process,dialysate flow may be between 250-5000 ml/min, preferably between1000-2000 ml/min. It may be useful to decouple the two circuits by adialysate reservoir, as in the dialysate regeneration unit the dialysisfluid has non-physiological pH and temperature values which would resultin great damage to the patient's blood. The dialysis fluid contained inthe dialysate reservoir 57 may either be cleaned in a continuousoperation or in an intermittent operation.

1. A dialysate regeneration unit (19, 64) for regenerating a dialysatecontaining carrier substances, with a first flow path (27) comprising afirst supply unit adapted for adding an acidic fluid (29) to thedialysate flowing in the first flow path (27), a detoxification unitlocated downstream of the first supply unit, the detoxification unitbeing adapted for removing toxins from the acidified dialysate flowingin the first flow path (27), a second flow path (28) that extends inparallel to the first flow path (27), the second flow path (28)comprising a second supply unit adapted for adding an alkaline fluid(31) to the dialysate flowing in the second flow path (28), a furtherdetoxification unit located downstream of the second supply unit, thefurther detoxification unit being adapted for removing toxins from thealkalised dialysate flowing in the second flow path (28).
 2. Thedialysate regeneration unit of claim 1, wherein the acidic fluid addedby the first supply unit comprises at least one of: hydrochloric acid,sulfuric acid, acetic acid.
 3. The dialysate regeneration unit of claim1, wherein the alkaline fluid added by the second supply unit comprisesat least one of: sodium hydroxide solution, potassium hydroxidesolution.
 4. The dialysate regeneration unit of claim 1, wherein thefirst supply unit is adapted for adjusting the pH of the dialysate inthe first flow path to a pH between 1 and 7, preferably between 2.5 and5.5.
 5. The dialysate regeneration unit of claim 1, wherein the secondsupply unit is adapted for adjusting the pH of the dialysate in thesecond flow path to a pH between 7 and 13, preferably between 8 and 13.6. The dialysate regeneration unit of claim 1, wherein by decreasing thepH of the dialysate in the first flow path, a concentration ratio oftoxin-carrier-complex to free toxin and free carrier substance isshifted in favour of the free toxin for at least some of the toxins inthe dialysate, thereby increasing a concentration of free toxins in thedialysate.
 7. The dialysate regeneration unit of claim 6, wherein thedetoxification unit is adapted for at least partially removing said freetoxins.
 8. The dialysate regeneration unit of claim 1, wherein byincreasing the pH of the dialysate in the second flow path, aconcentration ratio of toxin-carrier-complex to free toxin and freecarrier substance is shifted in favour of the free toxin for at leastsome of the toxins in the dialysate, thereby increasing a concentrationof free toxins in the dialysate.
 9. The dialysate regeneration unit ofclaim 8, wherein the further detoxification unit is adapted for at leastpartially removing said free toxins.
 10. The dialysate regeneration unitof claim 1, wherein at least one of the first and the second flow pathcomprises a temperature regulation unit located upstream of thedetoxification unit, the temperature regulation unit being adapted forincreasing or decreasing the temperature of the dialysate.
 11. Thedialysate regeneration unit of claim 10, wherein by changing, e.g.increasing, the temperature of the dialysate, the concentration ratio oftoxin-carrier-complex to free toxin and free carrier substance isshifted in favour of the free toxin for at least some of the toxins inthe dialysate, thereby increasing a concentration of free toxins in thedialysate.
 12. The dialysate regeneration unit of claim 1, wherein thetoxins comprise one or more of: metabolism products, bilirubin, bileacid, drugs, electrolytes, hormones, lipids, vitamins, phenols,sulfates, trace elements, minerals, gases.
 13. The dialysateregeneration unit of claim 1, wherein the carrier substances compriseone or more of: proteins, e.g. albumin, human serum albumin, animalalbumin, genetically engineered albumin, globulins, lipoproteins; carbonparticles glycosides; nucleic acids (and their derivatives); fattyacids; fats; carbon molecules; nanoparticles; memory plastics; memorymetals; resins; secondary plant substances or other complex compoundsderived from natural sources; carbon hydrates or synthetic compounds,e.g. polymers.
 14. The dialysate regeneration unit of claim 1, whereinthe detoxification unit and the further detoxification unit areimplemented as regeneration dialyzers, or as ultrafiltration devices, oras diafiltration devices.
 15. The dialysate regeneration unit of claim1, wherein the detoxification unit and the further detoxification uniteach comprise a filtration pump and a discharge conduit adapted forwithdrawing a discharge fluid from the respective detoxification unit.16. The dialysate regeneration unit of claim 1, wherein the first flowpath comprises a first pump adapted for pumping the dialysate throughthe first flow path, and wherein the second flow path comprises a secondpump adapted for pumping the dialysate through the second flow path, thefirst and the second pump operating independently of one another. 17.The dialysate regeneration unit of claim 1, wherein the acidifieddialysate supplied by the first flow path is merged with the alkaliseddialysate supplied by the second flow path.
 18. The dialysateregeneration unit of claim 1, wherein, when the acidified dialysatesupplied by the first flow path is merged with the alkalised dialysatesupplied by the second flow path, the acidified dialysate and thealkalised dialysate neutralize each other at least partially.
 19. Thedialysate regeneration unit of claim 1, wherein by merging the acidifieddialysate supplied by the first flow path with the alkalised dialysatesupplied by the second flow path, a flow of regenerated dialysate with apH value between 6 and 8, further preferably between 6.9 and 7.6, isobtained.
 20. The dialysate regeneration unit of claim 19, furthercomprising at least one sensor unit adapted for determining a pH valueof the flow of regenerated dialysate.
 21. The dialysate regenerationunit of claim 1, wherein the dialysate regeneration system comprises aplurality of switching valves.
 22. The dialysate regeneration unit ofclaim 21, wherein during a first phase of operation, the switchingvalves are set such that a first detoxification unit is included in thefirst flow path and that a second detoxification unit is included in thesecond flow path, whereas during a second phase of operation, theswitching valves are set such that the second detoxification unit isincluded in the first flow path and that the first detoxification unitis included in the second flow path.
 23. The dialysate regeneration unitof claim 21, wherein the switching valves are operated such that theacidified dialysate is alternatingly supplied to a first detoxificationunit and to a second detoxification unit, whereas the alkaliseddialysate is alternatingly supplied to the second detoxification unitand to the first detoxification unit.
 24. The dialysate regenerationunit of claim 21, wherein the switching valves are switchedperiodically.
 25. The dialysate regeneration unit of claim 21, whereinthe switching valves are automatically switched at regular timeintervals, preferably every 1 to 60 minutes.
 26. A dialysis systemcomprising a biological fluid circuit (11, 53), a dialysate circuit, atleast one dialyzer (12A, 12B, 54A, 54B), a dialysate regeneration unit(19, 64) according to claim
 1. 27. The dialysis system of claim 26,wherein the biological fluid is blood or blood plasma.
 28. The dialysissystem of claim 26, further comprising a dialysate reservoir that ispart of the dialysate circuit, wherein the dialysate regeneration unitis adapted for withdrawing dialysate from the dialysate reservoir, forregenerating the dialysate, and for resupplying the regenerateddialysate to the dialysate reservoir.
 29. The dialysis system of claim28, wherein the dialysate regeneration unit is part of a separatedialysate regeneration circuit.
 30. The dialysis system of claim 28,wherein the regeneration unit is adapted for regenerating the dialysatein a continuous operation or in an intermittent operation.
 31. Thedialysis system of claim 26, wherein the dialysate regeneration unit isintegrated into the dialysate circuit.
 32. The dialysis system of claim26, wherein the dialyzer comprises a biological fluid compartment thatis part of the biological fluid circuit, a dialysate compartment that ispart of the dialysate circuit, and a semipermeable membrane separatingthe biological fluid compartment and the dialysate compartment.
 33. Thedialysis system of claim 26, further comprising a substitution unitadapted for supplying substitution fluid to the biological fluid or tothe dialysate.
 34. The dialysis system of claim 33, wherein thesubstitution fluid comprises one or more of: electrolyte, nutrient,buffer.
 35. A method for regenerating a dialysate containing carriersubstances, the method comprising splitting a flow of dialysate into afirst flow and a second flow, adding an acidic fluid (29) to the firstflow of dialysate, removing toxins by filtrating, dialysing,precipitating or diafiltrating the acidified first flow of dialysate,adding an alkaline fluid (31) to the second flow of dialysate, removingtoxins by filtrating, dialysing, precipitating or diafiltrating thealkalized second flow of dialysate, merging the first and the secondflow of dialysate.
 36. The method of claim 35, further comprisingperiodically switching a plurality of switching valves such that theflow of acidified dialysate is alternatingly supplied to a firstdetoxification unit and to a second detoxification unit, whereas theflow of alkalized dialysate is alternatingly supplied to the seconddetoxification unit and to the first detoxification unit.
 37. The methodof claim 35, further comprising one or more of the following: regulatingthe temperature of the acidified dialysate; removing toxins byprecipitation due to the acidification; regulating the temperature ofthe alkalized dialysate; removing toxins by precipitation due to thealkalization.